Magnetization Transfer Study of Bipolar Disorder Abstract The disease mechanism of bipolar disorder remains largely unknown. However, recent data suggest that pathogenic alterations in cerebral bioenergetics pathways may be linked to bipolar disorder, especially in patients expressing symptoms of depression. In such patients, magnetic resonance spectroscopy (MRS) studies have consistently found decreases in phosphocreatine (PCr) levels, PET and SPECT studies have often reported cerebral energetic alterations and mitochondrial pathology. Furthermore, molecular genetics studies have reported decreases in the mRNA expression of creatine kinase (CK), the enzyme that facilitates the reversible transfer of a phosphate group from PCr to ADP, resulting in ATP. While important, measurements of static concentrations of metabolites and mRNA expression alone are not sufficient for characterization of a dynamic metabolic pathway. Quantitative analysis of potentially retarded reaction rates and associated fluxes are needed to accurately describe the mechanisms of this energy system. We propose to non-invasively measure the forward rate constant (kfor) of brain CK in 36 patients suffering from bipolar depression using magnetization transfer-31P MRS. Age and sex matched healthy control subjects (n=18) will undergo the same measurement for comparison. To increase patient homogeneity while maintaining feasibility of patient recruitment, our exploratory study will be performed on type II bipolar patients who are on either divalproex or lithium in conjunction with either no or limited use of antidepressants. Our preliminary data demonstrate that we have the technologies and subject resources to complete the proposed study. We hypothesize that 1) CK enzymatic activity, measured as kfor, in the frontal lobe of depressed BPD subjects will be decreased relative to that of age and sex matched controls;2) the kfor of CK will be negatively associated with depression severity in bipolar patients. Should the hypotheses prove to be correct, it will be of importance to the understanding of brain bioenergetic alterations as it relates to the disease mechanism of bipolar disorder. Furthermore, Positive results of the hypotheses on alterations in cerebral bioenergetics pathways could prompt the development of new treatment strategies. PUBLIC HEALTH RELEVANCE: Successful completion of this study will provide further insight into the disease mechanism of bipolar disorder, especially in older adults who are often treatment refractory bipolar patients, demonstrating the relevance of the altered bioenergtic model of the disease. Positive results of the hypotheses on alterations in cerebral bioenergetics pathways could prompt the development of new treatment strategies.